While changes in body composition-and often disastrous sequelae thereof-universally accompany old age, there is tremendous variability in their onset, pattern and severity. The long term objective of this project is to better understand the molecular basis for this heterogeneity, and thereby the pathways which underlie such changes. The immediate focus is whether some variability is due to genetic heterogeneity in the nuclear receptor RXRalpha (9-cis retinoic acid receptor). RXRalpha is essential for the action of many nuclear receptors (e.g. PPAR, THR, RAR) and lays significant roles in development and maintenance of bone, muscle and skin tissue (among other tissues). Ligand and artificial mutation suggest that alterations in RXRalpha activity or interactivity could have a variety of phenotypic consequences. We hypothesize that mutations in genes such as RXRalpha could contribute to (or protect against) severe or early onset declines in bone, muscle or skin. Specific aim #1 is to recruit small cohorts of well-characterized older individuals free of confounding conditions (e.g. glucocorticoid use) selected for severe and/or early onset: (i) osteoporosis, (ii) muscle weakness, (iii) decreased skin integrity, or (iv) absence of these at extreme old age. Specific Aim #2 is to perform SSCP analysis of RXRalpha on genomic DNA from 15 individuals of each cohort, and begin characterization of any variants identified. Beyond the scope of this pilot project is (i) screening these cohorts for variation in other genes that may influence musculoskeletal or dermatologic changes with age; (ii) performing functional analyses of large definitive association studies with any variants found from this screen; or (iii) assessing other conditions potentially influenced by variation in RXRalpha (e.g. thyroid function, vision). However, this project should form bases from which such questions could be explored. Within its scope, it may help to elucidate general pathways underlying age-related changes in body composition/function, which ultimately will lead to improved means of preventing and treating their sequelae (perhaps with the RXRalpha agonists/antagonists now being developed).